Iodinated contrast agents are well-known compounds widely used in x-ray imaging diagnostic techniques. Suitable examples of the said compounds include, for instance, diatrizoate, iothalamate, ioxithalamate, metrizoate, iohexol, iomeprol, iopamidol, iopentol, iopromide, ioversol, ioxilan, iodixanol, iosarcol, iogulamide, ioglunide, iogluamide, acetrizoate, iodamide, iocetamide and metrizamide, all having a monomeric structure, and ioxaglate, iotrolan, iotasul, iodipamide, iocarmate, iodoxamate, iotroxate, iotrolan, and the like, that, instead, are dimers. Additional examples of iodinated contrast agents are described, for instance, in WO 94/14478 (Bracco).
As a common feature, their chemical structure shares a triiodinated aromatic nucleus which provides the enhanced contrast effect.
The said compounds may be prepared by a variety of routes, that generally include the iodination of given aromatic substrates, for instance of suitable 3,5-disubstituted phenols, which undergo triiodination on the available 2, 4 and 6 positions, thus leading to the corresponding 3,5-disubstituted-2,4,6-triiodophenols. These latter, in turn, may be further converted and processed through the so-called Smile's rearrangement, to the expected final compounds.
For a general reference to the above synthetic route and Smile's rearrangement see, for instance, WO 88/09328, WO 97/05097 and WO 00/32561 (Bracco).
Alternatively, the aromatic iodination may be performed on suitable anilines, so as to provide the corresponding 2,4,6-triiodoaniline derivatives, to be further converted and processed to the final radiographic agent, for instance as disclosed in U.S. Pat. No. 5,075,502.
The iodination step may be performed utilizing different procedures.
In this regard, in industrial processes currently used for preparing the above radiographic contrast agents, the iodination of the aromatic ring is generally carried out by using solutions of iodine mono-chloride (ICl) in concentrated hydrochloric acid (HCl) (44.5% I and 14% HCl) at high temperature (about 90° C.) or, alternatively, by means of analogous iodinating agents such as, for instance, KICl2 or NaICl2 in aqueous solution; see, for a general reference, WO 92/14695 (Guerbet), U.S. Pat. No. 5,013,865 (Mallinckrodt), WO 96/37458 and WO 96/37459 (Fructamine).
The above methods suffer from major drawbacks due to the extremely acidic working conditions, that become harder due to HCl produced during the reaction, and to the corrosive properties and the limited storage life of the iodinating agents.
In addition, relevant problems mainly arise from the presence of chlorine atoms within the iodinating agents themselves, (formed at the high reaction temperature needed for the exhaustive iodination of aniline substrates), that may lead to the formation of hardly removable chlorinated side-products, which may thus affect reaction yields and purity of the final compounds.
On the other side, and from a different point of view, it is an increasingly recognized need to have industrial manufacturing processes which can combine low production costs, high production efficiency and minimized environmental impact.
Thus, attempts have been devoted to address new iodination methods based on the use of iodinating agents alternative to iodine mono-chloride or derivatives thereof.
Among them are, for instance, the electrochemical iodination processes of 3,5-disubstituted anilines or of given 3,5-disubstituted phenols, as disclosed in WO 96/37461 and WO2009/103666, respectively.
Beside the above approaches, the alternative iodination of aromatic nuclei with iodine suitably activated with an oxidizing agent has also been experienced.
For instance, the iodination of given phenol derivatives, referred to as ortho-hydroxy substituted aromatic carbonyl compounds, in the presence of molecular iodine activated with a strong oxidizing agent, including iodic acid, has been described by Patil et al. in Tetrahedron Letters 2005, 46, 7179-7181, and in ARKIVOC 2006, 104-108.
This art is, however, silent on the possibility of exploiting that disclosed synthetic approach, namely the combined use of molecular iodine and an oxidizing agent, to iodinate or poly-iodinate aniline or aniline derivatives.
US 2007/0219396 discloses a method for producing 2-amino-5-iodobenzoic acid by iodination of 2-aminobenzoic acid, solubilized in acetic acid, with iodine and in the presence of an oxidizing agent, especially hydrogen peroxide.
This application, however, does not mention or suggest the possibility of exploiting the disclosed procedure to provide poly-iodinated compounds and, in particular, triiodinated aniline derivatives that, indeed, would hardly have been achieved under the disclosed iodination conditions, as evidenced by the Comparative Example 1 of the following experimental section.
The use of iodine and iodic acid to produce 3-amino-2,4,6-triiodobenzoic and 3,5-diamino-2,4,6-triiodobenzoic acids is also mentioned in Chem. Ber., 1897, 30 (2), 1943-1948 and in Chem. Ber., 1896, 29 (3), 2833-2839, respectively.
These references, however, are quite deficient in the full description of the iodinating conditions used, so as to prevent their accurate reproduction.
In any case, the disclosed iodinating conditions and the amount of iodinating agent, in particular of iodic acid, seems far to be sufficient to allow triiodination of the substrate, at least with appreciable yield and purity, as discussed in greater detail in the Comparative Example 2 of the experimental section below.
Moreover, in both of the cited articles, the obtained brown precipitate needs to be washed with sulfuric acid, solubilized in diluted ammonia and then precipitated with sulfuric acid to have a product of the desired purity.
In this respect, it is worth noting that the use of strong oxidizing conditions with aniline or even halogenated anilines is known to lead to the formation of mixtures of colored by-products, mainly azo-compounds deriving from oxidative coupling reactions involving the aromatic amino group (see, for instance, Erich Baer and Anthony L. Tosoni, J. Am. Chem. Soc., 1956, 78 (12), 2857-2858), while all the above art does neither address nor even suggest how to solve this problem.
For contrast, the need of collecting process intermediates and final compounds with a high degree of purity is of utmost importance in order to optimize, to a significant extent, the purification steps required for the final agent, that has to be in compliance with the strict purity profile and limits imposed by the Pharmacopoeia, in particular for products intended for the administration.
For instance, the analytical specifications fixed by the EP Pharmacopoeia for the 5-amino-2,4,6-triiodoisophthalic acid, are:
Loss on drying ≦3.5%
Title: 98.0-102%
Ashes: ≦1.0%
Total related substances: ≦1% (intended as the sum of all known and unknown impurities, mainly represented by partially iodinated compounds and chlorinated compounds) of which the sum of the chlorinated impurities must be ≦0.35%.
We have now found that the triiodination of suitable 3,5-disubstituted anilines can be advantageously carried out in high yields and purity by using a iodinating system comprising molecular iodine and an oxidizing agent overcoming the above major drawbacks.